The present invention relates to medical treatments for psychiatric disorders. More specifically, it is concerned with novel methods and compositions for treating patients with bipolar disorder.
Patients with bipolar disorder suffer recurrent, alternating cycles of mania and depression. In a controlled clinical study performed more than a decade ago, it was reported that lecithin (phosphatidylcholine) has anti-manic properties when administered to such patients (Cohen et al., Am. J. Psychiatry 139:1162-1164 (1982); see also Cohen et al., Am. J. Psychiatry 137:242-243 (1980); Schreier, Am. J. Psychiatry 139:108-110 (1982)). More recent reports, have suggested that the beneficial effects observed for lecithin are due primarily to the metabolic release of free choline (Stoll et al., Biol. Psychiatry 37:170-174 (1995)).
Although effective in reducing mania, lecithin is not widely used in treating bipolar patients. One of the main reasons for this is that 15-30 grams of lecithin per day must typically be given to a patient in order to obtain a beneficial effect, and the intake of such a large quantity of lipid would, over time, tend to promote cardiovascular disease. An ideal solution to this problem would be to administer a therapeutic agent that has the same beneficial effect as lecithin in controlling mania but which does not have the same adverse effect with respect to cardiovascular disease.
The present invention is directed to phosphatidylcholines in which the xcex1 or xcex2 carbon of glycerol is esterified to an omega-3 fatty acid. These fatty acids are unique among dietary fats in that they inhibit thrombosis and platelet aggregation and can lower blood pressure (see Dimmitt, Clin. Exp. Pharmacol. Physiol. 22:204-208 (1995)). Thus, the xe2x80x9comega-3 phosphatidylcholinesxe2x80x9d disclosed herein produce the same effects as lecithin in bipolar patients due to the release of free choline but reduce, rather than increase, the risk that a patient will suffer a stroke or coronary thrombosis.
In addition, the present invention is directed to a method of treating bipolar disorder using omega-3 fatty acids themselves, i.e. apart from phosphatidylcholine. These may be administered in a purified state, as part of a composition containing other therapeutic agents or as part of another compound, e.g. a triacylglycerol, which is metabolized to release free fatty acid in vivo.
An evaluation of mood stabilizing agents indicates that all such agents presently used to treat bipolar patients have an inhibitory effect on neuronal signal transduction systems. The present invention is based, in part, upon this discovery and the upon the recognition that omega-3 fatty acids are useful in treating pathological conditions involving excessive cell signal transduction (see e.g., Sperling, Rheum. Dis. Clinics 17 (1991); Sperling, et al., J. Clin. Invest. 91:651-660 (1993)).
Thus, a method has been developed for treating a human patient for bipolar disorder by administering omega-3 fatty acids at a dosage sufficient to reduce or eliminate the symptoms associated with the disorder, i.e. at a dosage sufficient to reduce the frequency of mood fluctuations or lessen the severity of the mania or depression experienced by such patients. The omega-3 fatty acids should be administered at a dosage of between about 1 and about 30 grams per day. The two most preferred omega-3 fatty acids are eicosapentanoic acid and docosahexanoic acid and these should typically be administered at daily dosages of 2-10 grams and 1-5 grams respectively. The fatty acids may be administered as the sole therapeutic agent or in conjunction with other agents known to be useful in the treatment of bipolar patients. In particular, the fatty acids may be administered with a source either of lithium or choline. In addition, omega-3 fatty acids may be taken by patients as a component of another molecule, e.g. a triacylglycerol, and be metabolically released after ingestion.
The present invention is also directed to an omega-3 phosphatidylcholine useful in the treatment of bipolar disorder, consisting of glycerol esterified at both its xcex1 and xcex2 carbons to fatty acids. At least one, and preferably both, of these fatty acids is an omega-3, fatty acid and the xcex3 position of the glycerol must be esterified to phosphocholine. It is preferred that at least one of the esterified fatty acids be either eicosapentanoic acid or docosahexanoic acid. Omega-3 phosphatidylcholines with eicosapentanoic acid esterified to the xcex1 carbon and docosahexanoic acid esterified to the xcex2 carbon and vice versa are the most preferred. In all cases, the xcex3 position of the triacylglycerol is esterified to phosphocholine.
In another aspect, the present invention is directed to a pharmaceutical composition comprising one or more of the omega-3 phosphatidylcholines discussed above. The composition should contain sufficient triacylglycerol so that one or more unit doses provides enough agent to reduce or eliminate the symptoms associated with bipolar disorder. In some instances, lithium may be also incorporated into the composition in order to improve therapeutic effects.
The present invention is also directed to a method for treating bipolar disorder in a human patient by administering an omega-3 phosphatidyicholine. It is expected that this phosphatidylcholine will typically be administered at a dosage sufficient to provide between 1 and 30 (preferably between 2 and 8) grams of free omega-3 fatty acid to the patient. Again, administration may be carried out concurrently with the administration of other therapeutic agents such as lithium.